Viruses have evolved a variety of mechanisms to escape antibody recognition, many of which involve features of the viral surface proteins, such as high variability, steric occlusion, and glycan coating. For HIV, the dense shield of glycans that decorate the viral Env protein was once believed to be refractory to antibody recognition, shielding conserved protein epitopes of important functional significance whose greater exposure would result in increased susceptibility to antibody neutralization.
However, bnMAb 2G12 and several PGT antibodies appear to bind directly to the HIV glycan coat. Although carbohydrate-protein interactions are typically weak, 2G12 recognizes terminal Manα1,2Man moieties on oligomannose glycans using a unique domain-exchanged antibody structure that creates a multivalent binding surface and enhances the affinity of the interaction through avidity effects.
However, although 2G12 neutralizes clade B isolates broadly, it is less effective against other clades, in particular clade C viruses that have a somewhat different oligomannose glycan arrangement to clade B viruses. In contrast, Applicants have recently isolated at least six bnMAbs (PGTs 125-128, 130-131) that bind specifically to the Man8/9 glycans on gp120 and neutralize across clades with exceptional breadth and potency. PGT 128, the broadest of these antibodies, neutralizes over 70% of globally circulating viruses and is, on average, an order of magnitude more potent than the recently described PG9, PG16, VRC01, and VRC-PG04 bnMAbs and two orders of magnitude more potent than prototype bnMAbs described earlier.
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